The burden of non‐SARS‐CoV2 viral lower respiratory tract infections in hospitalized children in Barcelona (Spain): A long‐term, clinical, epidemiologic and economic study

Abstract Background Viral lower respiratory tract infections (LRTI) are the leading cause of hospitalization in children. In Catalonia (Spain), information is scarce about the burden of viral LRTIs in paediatric hospitalizations. The aim of this study is to describe epidemiological, clinical, virological and economic features of paediatric hospitalizations due to viral LRTI. Methods From October 2012 to December 2020, children aged <16 years admitted to a tertiary paediatric hospital in Catalonia (Spain) with confirmed viral LRTI were included in the study. Virus seasonality, prevalence, age and sex distribution, clinical characteristics, hospital costs and bed occupancy rates were determined. Results A total of 3,325 children were included (57.17% male, 9.44% with comorbidities) accounting for 4056 hospitalizations (32.47% ≤ 12 months): 53.87% with wheezing/asthma, 37.85% with bronchiolitis and 8.28% with pneumonia. The most common virus was respiratory syncytial virus (RSV) (52.59%). Influenza A was associated with pneumonia (odds ratio [OR] 7.75) and caused longer hospitalizations (7 ± 31.58 days), while RSV was associated with bronchiolitis (OR 6.62) and was the most frequent reason for admission to the paediatric intensive care unit (PICU) (11.23%) and for respiratory support (78.76%). Male sex, age ≤12 months, chronic conditions and bronchiolitis significantly increased the odds of PICU admission. From October to May, viral LRTIs accounted for 12.36% of overall hospital bed days. The total hospitalization cost during the study period was €16,603,415. Conclusions Viral LRTIs are an important cause of morbidity, hospitalization and PICU admission in children. The clinical burden is associated with significant bed occupancy and health‐care costs, especially during seasonal periods.

associated with pneumonia (odds ratio [OR] 7.75) and caused longer hospitalizations (7 ± 31.58 days), while RSV was associated with bronchiolitis (OR 6.62) and was the most frequent reason for admission to the paediatric intensive care unit (PICU) (11.23%) and for respiratory support (78.76%). Male sex, age ≤12 months, chronic conditions and bronchiolitis significantly increased the odds of PICU admission. From October to May, viral LRTIs accounted for 12.36% of overall hospital bed days. The total hospitalization cost during the study period was €16,603,415.
Conclusions: Viral LRTIs are an important cause of morbidity, hospitalization and PICU admission in children. The clinical burden is associated with significant bed occupancy and health-care costs, especially during seasonal periods.  1 The most common LRTIs in children are bronchiolitis, community acquired pneumonia (CAP), wheezing and asthma exacerbation. [2][3][4] Bronchiolitis is a viral infection with an annual incidence of 5.2/100 in children under six months of age in Spain, and an annual hospitalization incidence of 2.1 cases/100 children per year. 2 It is responsible for up to 13.5% of paediatric intensive care unit (PICU) admissions during the winter months. 5 The main etiological agent of bronchiolitis is the respiratory syncytial virus (RSV), followed by the rhinovirus (RV). 5 CAP is also a major cause of illness in children in developed countries. A virus is identified in 43-67% of cases of CAP, with RV, RSV, and influenza viruses being the main culprits worldwide. 3 Finally, 30-50% of children suffer one episode of wheezing before school age, and 30-40% present recurrent episodes. Asthma is the leading cause of chronic disease worldwide, with a prevalence of 10% in Western Europe. 4 Both diseases can be triggered by viral infection, with RV being the most common etiological agent, followed by RSV. 4 The introduction of molecular testing as standard laboratory practice to determine the presence RSV, influenza, and other respiratory viruses has led to a better understanding of the burden of viral LRTIs in hospitalized children. Interest in respiratory viral infections has been heightened during the COVID-19 pandemic; however, there is scant information about the surveillance of respiratory viruses other than RSV, influenza, and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in hospitalized paediatric patients. Viral LRTIs are not only interesting from a microbiological and clinical perspective, they also impact hospital bed occupancy rates and healthcare costs, and data on the latter can help hospital managers plan the distribution of their sources during annual epidemics. In this study, we analyse the demographic, clinical, and viral characteristics of LRTIs together with the cost of paediatric hospitalizations due to viral LRTI other than SARS-CoV-2 in a referral hospital in Southwestern Europe in order to improve understanding of the burden of viral LRTIs in hospitalized children. for patients suffering from oncohematologic diseases or some forms of rare diseases being the population covered actually higher than the above-mentioned.

| Study design and participants
All consecutive paediatric patients (<16 years old) with laboratory-confirmed viral LRTI other than SARS-CoV-2 who required hospitalization during the study period were included. Respiratory samples for laboratory confirmation were collected within 3 days before and 2 days after admission. The reason for hospitalization was considered to be an LRTI if, according to the International Classification of Diseases ninth (ICD-9) or tenth (ICD-10) revision (Table S1) Patients that met the inclusion criteria were classified in three groups according to the main clinical diagnosis: bronchiolitis-defined as the first episode of viral LRTI in an infant aged under 2 years as per our local protocol, 6 CAP and wheezing/asthma.  Flu/RSV XC, Cepheid, CA, USA). If the rapid test was negative, the study was extended to include other respiratory viruses that were detected using routine testing techniques.

| Statistical analysis
Continuous variables are described as mean and standard deviation (SD) and categorical variables as frequencies and proportions. Contingency tables were used to analyse the relationship between two qualitative variables, and chi-square tests were used to assess associations.
The Kruskal Wallis test was used to analyse the relationship between quantitative and qualitative variables. A logistic regression model was used to characterize the response variables, and the results were presented as an odds ratio (OR) with the corresponding 95% confidence interval (95% CI). A multivariate logistic regression model was used to determine the risk factors associated with PICU admission. In all models, pair-wise comparisons were performed using Tukey correction for multiple comparisons. The significance level was set at 0.05 for all tests. The results were analysed using SAS v9.4 (SAS Institute Inc., Cary, NC, USA).

| RESULTS
During the study period, 29,511 children aged <16 years were admit- To determine whether certain respiratory viruses were associated with specific LRTIs, we compared the number of patients who tested positive for each virus with those that tested negative for that virus ( Figure 1). FLUAV was associated with pneumonia (OR 7.75, 95% CI 5.24-11.49; p < 0.0001), RSV was associated with bronchiolitis (OR 3.57, 95% CI 3.13-4.17; p < 0.0001), and RV caused mainly wheezing/asthma (OR 3.58, 95% CI 3.07-4.18; p < 0.0001).
We also performed multivariate analyses to identify the host factors that increased the risk of PICU admission (Table S5): male sex (adjusted p = 0.0048), age ≤ 12 months (adjusted p = 0.0002 compared with 12-24 months), history of chronic conditions (adjusted p < 0.0001), and bronchiolitis (adjusted p = 0.0004). We were unable to confirm any correlation with viruses.     Before the COVID-19 pandemic, the burden of respiratory viruses was particularly high during the winter months in temperate countries such as Spain due to the annual RSV, influenza, and HMPV epidemics. 8  influenza viruses, and HMPV. [16][17][18] We, however, found that respiratory viruses other than RSV, influenza, and HMPV were responsible for a third of all cases of LRTIs, showing that the burden of these viruses is significant in terms of bed occupancy rates and healthcare costs. Overall, RSV has been described as the main cause of hospital admission and LRTI-related deaths worldwide, followed by influenza viruses, and HMPV, particularly in children aged <1 year. 1,16-18 RSV and influenza viruses were also the main causes of morbidity and mortality in our study, as both were associated with prolonged LOS. In the case of RSV, this was probably due to the need for respiratory support and PICU admission for bronchiolitis, 19 while in the case of influenza, it was likely due to the use of parenteral antibiotics and respiratory support for secondary bacterial infection in patients with CAP. 20 FLUAV and RSV were associated with the four fatalities in our study, all of which occurred in children with a history of comorbidities, as previously reported. 19,20 Despite the lower number of HMPV cases, the risk of severe infection has been described as similar to that of RSV or influenza viruses, especially in children aged <1 year. 17,21 However, we observed milder outcomes in HMPV infection, probably due to the lower proportion of children aged <1 year and to differences in HMPV genotypes circulating in each region. 9 RV, despite being the second most prevalent LRTI-related virus, caused milder disease compared with RSV or influenza viruses, probably due to less respiratory cytokine production leading to a milder proinflammatory response. 22 Our data showed that a high proportion of hCoV-and BoV-related LRTIs required PICU admission, and a high number of BoV-related infections required respiratory support, although this occurred mostly in cases of co-infection with more virulent viruses, such as RSV. 23

CONFLICT OF INTEREST
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or nonfinancial interest in the subject matter or materials discussed in this manuscript.

ETHICS STATEMENT
All procedures were performed in accordance with the ethical stan-

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13085.

DATA AVAILABILITY STATEMENT
Anonymized and de-identified participant data will be available upon request until 2 years after publication. Data will be available for researchers who provide a methodologically sound proposal. Requests may be sent to the corresponding author, and to gain access data requestors will need to sign a data access agreement.